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MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria
Authors:Qiu-li Zhang  Bai-ri Cui  Hai-yan Li  Ping Li  Lan Hong  Li-ping Liu  Da-zhi Ding  Xun Cui
Institution:1. Department of Physiology, School of Medical Sciences, Yanbian University, Yanji 133-002, China;2. Key Laboratory of Organism Functional Factors of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133-002, China;3. Cellular Function Research Center, Yanbian University, Yanji 133-002, China;4. Institute of Clinical Medicine, Yanbian University, Yanji 133-000, China;5. Affiliated Hospital of Inner Mongolia University for the Nationalities, No. 1742, HuoLinHe Street, Tongliao, Neimenggu 028050, China
Abstract:Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are pivotal and intensively studied signaling pathways in hypoxic conditions. However, the roles of MAPK and PI3K in the regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion are not well understood. The purpose of the present study was to investigate the mechanism by which the MAPK/ERK (extracellular signal-regulated kinase) and PI3K signaling pathways regulate the acute hypoxia-induced ANP secretion in isolated beating rabbit atria. An acute hypoxic perfused beating rabbit atrial model was used. The ANP levels in the atrial perfusates were measured by radioimmunoassay, and the hypoxia-inducible factor-1α (HIF-1α) mRNA and protein levels in the atrial tissue were determined by RT-PCR and Western blot. Acute hypoxia significantly increased ANP secretion and HIF-1α mRNA and protein levels. Hypoxia-induced ANP secretion was markedly attenuated by the HIF-1α inhibitors, rotenone (0.5 μmol/L) and CAY10585 (10 μmol/L), concomitantly with downregulation of the hypoxia-induced HIF-1α mRNA and protein levels. PD098059 (30 μmol/L) and LY294002 (30 μmol/L), inhibitors of MAPK and PI3K, markedly abolished the hypoxia-induced ANP secretion and atrial HIF-1α mRNA and protein levels. The hypoxia-suppressed atrial dynamics were significantly attenuated by PD098059 and LY294002. Acute hypoxia in isolated perfused beating rabbit atria, markedly increased ANP secretion through HIF-1α upregulation, which was regulated by the MAPK/ERK and PI3K pathways. ANP appears to be part of the protective program regulated by HIF-1α in the response to acute hypoxic conditions.
Keywords:Atrial natriuretic peptide (ANP)  Acute hypoxia  Hypoxia-inducible factor-1 (HIF-1)  Mitogen-activated protein kinase (MAPK)  Phosphatidylinositol 3-kinase (PI3K)
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